The National Human Genome Research Institute will issue multiple FOAs to fund a Human Genome Reference Program (HGRP) that is intended to replace and update its current commitment to activities now undertaken by the Genome Reference Consortium (GRC). The GRC provides a resource used by essentially all researchers who need to align and read-map experimental or patient genome sequence data. It also serves as a consensus coordinate system for reporting results. The GRC improves the reference, curates and releases updates and new reference builds, develops representations and alignment tools so that the community can use the reference and alternative haplotype information within it, resolves error reports from the community, and performs outreach. The GRC operates as an international consortium, with support provided by NHGRI, as well as the Wellcome Trust and the National Center for Biotechnology Information.

The expected application due date is in winter 2019.

This FOA will utilize the UM1 activity code. Details of the planned FOA are provided below.

Research Initiative Details

This Notice of Intent covers one component of this overall activity, the production of High Quality Human Reference Genomes (HQRG). The FOA will be released in conjunction with at least two other FOAs, one for a Human Genome Reference Center (HGRC), and one for Research and Development for Genome Reference Representations. NHGRI intends to also fund related activities in Research and Development for Comprehensive Genome Sequencing and Informatics Tools for the Pan-Genome. The awards under these FOA will constitute the NHGRI Human Genome Reference Program (HGRP). Successful applicants for this and related FOA are expected to collaborate with each other, and with other international resources and efforts related to genomic references. NHGRI will seek competitive applications from all eligible institutions, whether currently supported for human genome reference activities or not.

As an outgrowth of the International Human Genome Project, the current human genome reference has sustained and supported genomic research for more than the last decade. However, there is need for improvement in several areas. First, the reference does not adequately represent human population genetic diversity. This will result in suboptimal ability to map short read genome sequencing data to the reference, in a way that is biased to favor the populations already represented in the reference. Second, we need improved approaches for representing variation from multiple individual sequences, in order to fully capture human diversity in a “pangenome”, improve how that information is represented, and to ease computation and downstream use. Third, the community of users of the reference continues to expand and diversify, meaning that new informatics tools will need to be developed to make the reference easily usable for multiple communities.

For this specific FOA, the HQRG will produce up to 350 haplotype-resolved human genomes, using diverse samples consented for full data release. Awardees will initially use 1000 Genomes Project samples. The awardee will also be expected coordinate the consent and collection of new samples, if they are needed to obtain appropriate haplotype diversity, as determined by the HGRP. Sample selection and prioritization will be done together with the HGRC. The HQRG may also provide capacity to help resolve error reports received by the HGRC.

Applicants should plan to propose quality metrics for new high-quality genome assemblies for addition to the human reference, balancing costs/funds available, and use of best available technologies (e.g. a mix of short-read, long-read, synthetic long-read, optical mapping, etc.) to achieve those metrics. However, the appropriate metrics are still partly an open scientific question, and we anticipate that metrics will be established through discussion within the HGRP as a whole before significant data production begins. Moreover, sequencing technologies, cost, required quality, and added value of new genomes will be assessed by the program over the course of the project, as these considerations are expected to change over time. Funding, or specific uses of the capacity, may be adjusted accordingly.

In general, this program will not directly support genome reference work on other than human.

NHGRI anticipates making a single award for this FOA; therefore applications will need to address all of the factors mentioned above.

Funding Information

Estimated Total Funding NHGRI intends to commit up to $3,500,000 total costs per year for the first year.
The application budgets must reflect the actual needs of the proposed project, but are not limited.Expected Number of Awards One award will be made.Estimated Award Ceiling Budgets must reflect the actual needs of the proposed project, but are not limited. Primary CFDA Numbers 93.172